Melanopsin-expressing intrinsically photosensitive retinal ganglion cells in retinal disease

Melanopsin containing intrinsically photosensitive Retinal Ganglion Cells (ipRGCs) are a class of photoreceptors with established roles in non-image forming processes. Their contributions to image forming vision may include the estimation of brightness. Animal models have been central for understanding the physiological mechanisms of ipRGC function and there is evidence of conservation of function across species. ipRGCs can be divided into 5 ganglion cell subtypes that show morphological and functional diversity. Research in humans has established that ipRGCs signal environmental irradiance to entrain the central body clock to the solar day for regulating circadian processes and sleep. In addition, ipRGCs mediate the pupil light reflex (PLR), making the PLR a readily accessible behavioural marker of ipRGC activity. Less is known about ipRGC function in retinal and optic nerve disease, with emerging research providing insight into their function in diabetes, retinitis pigmentosa, glaucoma and hereditary optic neuropathy. We briefly review the anatomical distributions, projections and basic physiological mechanisms of ipRGCs, their proposed and known functions in animals and humans with and without eye disease. We introduce a paradigm for differentiating inner and outer retinal inputs to the pupillary control pathway in retinal disease and apply this paradigm to patients with age-related macular degeneration (AMD). In these cases of patients with AMD, we provide the initial evidence that ipRGC function is altered, and that the dysfunction is more pronounced in advanced disease. Our perspective is that with refined pupillometry paradigms, the pupil light reflex can be extended to AMD assessment as a tool for the measurement of inner and outer retinal dysfunction

The Effects of Short-Term Light Adaptation on the Human Post-Illumination Pupil Response

PURPOSE. We determine the effect of short-term light adaptation on the pupil light reflex and the melanopsin mediated post-illumination pupil response (PIPR). Inner and outer retinal photoreceptor contributions to the dark-adapted pupil response were estimated. METHODS. In Experiment A, light adaptation was studied using short wavelength lights ranging from subthreshold to suprathreshold irradiances for melanopsin signaling that were presented before (5-60 seconds) and after (30 seconds) a melanopsin-exciting stimulus pulse. We quantified the pupil constriction and the poststimulus response amplitudes during dark (PIPR) and light (poststimulus pupil response, PSPR) adaptation. In Experiment B, colored prestimulus adapting lights were univariant for melanopsin or rod excitation. RESULTS. Increasing the prestimulus duration and irradiance of adapting lights increased the pupil constriction amplitude when normalized to the dark-adapted baseline but reduced its amplitude when normalized to the light-adapted baseline. Light adaptation at irradiances suprathreshold for melanopsin activation increased the PIPR amplitude, with larger changes at longer adaptation durations, whereas the PSPR amplitude became more attenuated with increasing irradiances, independent of duration. Rod versus melanospin univariant adaptation did not alter the constriction amplitude but increased the PIPR amplitude in the rod condition. Correlations between millimeter pupil constriction and PIPR amplitudes were eliminated when normalized to the baseline diameter. CONCLUSIONS. The findings have implications for standardizing light adaptation paradigms and the choice of pupil metrics in both laboratory and clinical settings. Light and dark adaptation have opposite effects on the pupil metrics, which should be normalized to baseline to minimize significant correlations between constriction and PIPR amplitudes

Melanopsin-Mediated Post-Illumination Pupil Response in Early Age-Related Macular Degeneration

PURPOSE. To determine whether melanopsin-expressing intrinsically photosensitive retinal ganglion cell (ipRGC) inputs to the pupil light reflex (PLR) are affected in early age-related macular degeneration (AMD). METHODS. The PLR was measured in 40 participants (20 early AMD and 20 age-matched controls) using a custom-built Maxwellian view pupillometer. Sinusoidal stimuli (0.5 Hz, 11.9 seconds duration, 35.68 diameter) were presented to the study eye and the consensual pupil response was measured to lights with high melanopsin excitation (464 nm [blue]) and with low melanopsin excitation (638 nm [red]) that biased activation to the outer retina. Two melanopsin PLR metrics were quantified: the phase amplitude percentage (PAP) during the sinusoidal stimulus presentation and the post-illumination pupil response (PIPR). The PLR during stimulus presentation was analyzed using latency to constriction, the transient pupil response and maximum pupil constriction metrics. Diagnostic accuracy was evaluated using receiver operating characteristic (ROC) curves. RESULTS. The blue PIPR was significantly less sustained in the early AMD group (P < 0.001). The red PIPR was not significantly different between groups (P > 0.05). The PAP and blue stimulus constriction amplitude were significantly lower in the early AMD group (P < 0.05). There was no significant difference between groups in the latency or transient amplitude for both stimuli (P > 0.05). ROC analysis showed excellent diagnostic accuracy for the blue PIPR metrics (area under the curve > 0.9). CONCLUSIONS. This is the initial report that the melanopsin-controlled PIPR is dysfunctional in early AMD. The noninvasive, objective measurement of the ipRGC controlled PIPR has excellent diagnostic accuracy for early AMD

Melanopsin-Driven Pupil Response and Light Exposure in Non-seasonal Major Depressive Disorder

Background: Melanopsin-expressing intrinsically photosensitive Retinal Ganglion Cells (ipRGCs) signal non-imaging forming effects of environmental light for circadian phoentrainment, the pupil light reflex, and mood regulation. In seasonal affective disorder, ipRGC dysfunction is thought to cause abberant transmission of the external illumination for photoentrainment. It is not known if patients with non-seasonal depression have abnormal melanospin mediated signaling and/or irregular environmental light exposure.Methods: Twenty-one adults who live in a sub-tropical region, including eight patients with non-seasonal depression and thirteen age-matched healthy controls were recruited. The Mini International Neuropsychiatry Interview diagnosed the presence of a major depressive disorder. Light exposure was determined using actigraphy over a 2 week period. The melanopsin mediated post-illumination pupil response (PIPR) and outer retinal inputs to ipRGCs (transient pupil response and maximum pupil constriction amplitude) were measured in response to 1 s, short and long wavelength light with high and low melanopsin excitation.Results: The mean daylight exposure as a function of clock hours and total light exposure duration (mins) to illumination levels commonly recommended for depression therapy were not significantly different between groups. Out of 84 pupil measurements (42 each in the depression and control groups), the melanopsin-mediated PIPR amplitude, transient pupil response, and pupil constriction amplitude were not significantly different between groups.Conclusions: This report provides initial evidence of normal melanopsin function and environmental light exposures in patients with pre-dominately mid and moderate non-seasonal depression in a subtropical location in the southern hemisphere

Non-linearities in the Rod and Cone Photoreceptor Inputs to the Afferent Pupil Light Response

Purpose: To assess the nature and extent of non-linear processes in pupil responses using rod- and cone-isolating visual beat stimuli.Methods: A four-primary photostimulating method based on the principle of silent substitution was implemented to generate rod or cone isolating and combined sinusoidal stimuli at a single component frequency (1, 4, 5, 8, or 9 Hz) or a 1 Hz beat frequency (frequency pairs: 4 + 5, 8 + 9 Hz). The component frequencies were chosen to minimize the melanopsin photoresponse of intrinsically photosensitive retinal ganglion cells (ipRGCs) such that the pupil response was primarily driven by outer retinal photoreceptor inputs. Full-field (Ganzfeld) pupil responses and electroretinograms (ERGs) were recorded to the same stimuli at two mesopic light levels (−0.9 and 0 log cd/m2). Fourier analysis was used to derive the amplitudes and phases of the pupil and ERG responses.Results: For the beat frequency condition, when modulation was restricted to the same photoreceptor type at the higher mesopic level (0 log cd/m2), there was a pronounced pupil response to the 1 Hz beat frequency with the 4 + 5 Hz frequency pair and rare beat responses for the 8 + 9 Hz frequency pair. At the lower mesopic level there were few and inconsistent beat responses. When one component modulated the rod excitation and the other component modulated the cone excitation, responses to the beat frequency were rare and lower than the 1 Hz component frequency condition responses. These results were confirmed by ERG recordings.Conclusions: There is non-linearity in both the pupil response and electroretinogram to rod and cone inputs at mesopic light levels. The presence of a beat response for modulation components restricted to a single photoreceptor type, but not for components with cross-photoreceptor types, indicates that the location of a non-linear process in the pupil pathway occurs at a retinal site earlier than where the rod and cone signals are combined, that is, at the photoreceptor level

Standards in Pupillography

The number of research groups studying the pupil is increasing, as is the number of publications. Consequently, new standards in pupillography are needed to formalize the methodology including recording conditions, stimulus characteristics, as well as suitable parameters of evaluation. Since the description of intrinsically photosensitive retinal ganglion cells (ipRGCs) there has been an increased interest and broader application of pupillography in ophthalmology as well as other fields including psychology and chronobiology. Color pupillography plays an important role not only in research but also in clinical observational and therapy studies like gene therapy of hereditary retinal degenerations and psychopathology. Stimuli can vary in size, brightness, duration, and wavelength. Stimulus paradigms determine whether rhodopsin-driven rod responses, opsin-driven cone responses, or melanopsin-driven ipRGC responses are primarily elicited. Background illumination, adaptation state, and instruction for the participants will furthermore influence the results. This standard recommends a minimum set of variables to be used for pupillography and specified in the publication methodologies. Initiated at the 32nd International Pupil Colloquium 2017 in Morges, Switzerland, the aim of this manuscript is to outline standards in pupillography based on current knowledge and experience of pupil experts in order to achieve greater comparability of pupillographic studies. Such standards will particularly facilitate the proper application of pupillography by researchers new to the field. First we describe general standards, followed by specific suggestions concerning the demands of different targets of pupil research: the afferent and efferent reflex arc, pharmacology, psychology, sleepiness-related research and animal studies

The Circadian Response of Intrinsically Photosensitive Retinal Ganglion Cells

Intrinsically photosensitive retinal ganglion cells (ipRGC) signal environmental light level to the central circadian clock and contribute to the pupil light reflex. It is unknown if ipRGC activity is subject to extrinsic (central) or intrinsic (retinal) network-mediated circadian modulation during light entrainment and phase shifting. Eleven younger persons (18–30 years) with no ophthalmological, medical or sleep disorders participated. The activity of the inner (ipRGC) and outer retina (cone photoreceptors) was assessed hourly using the pupil light reflex during a 24 h period of constant environmental illumination (10 lux). Exogenous circadian cues of activity, sleep, posture, caffeine, ambient temperature, caloric intake and ambient illumination were controlled. Dim-light melatonin onset (DLMO) was determined from salivary melatonin assay at hourly intervals, and participant melatonin onset values were set to 14 h to adjust clock time to circadian time. Here we demonstrate in humans that the ipRGC controlled post-illumination pupil response has a circadian rhythm independent of external light cues. This circadian variation precedes melatonin onset and the minimum ipRGC driven pupil response occurs post melatonin onset. Outer retinal photoreceptor contributions to the inner retinal ipRGC driven post-illumination pupil response also show circadian variation whereas direct outer retinal cone inputs to the pupil light reflex do not, indicating that intrinsically photosensitive (melanopsin) retinal ganglion cells mediate this circadian variation

Adaptive bilateral filtering using saliency map for deblocking low bit rate videos

This paper proposes a novel approach to video deblocking which performs perceptually adaptive bilateral filtering by considering color, intensity, and motion features in a holistic manner. The method is based on bilateral filter which is an effective smoothing filter that preserves edges. The bilateral filter parameters are adaptive and avoid over-blurring of texture regions and at the same time eliminate blocking artefacts in the smooth region and areas of slow motion content. This is achieved by using a saliency map to control the strength of the filter for each individual point in the image based on its perceptual importance. The experimental results demonstrate that the proposed algorithm is effective in deblocking highly compressed video sequences and to avoid over-blurring of edges and textures in salient regions of image

Effect of optical aberrations on the color appearance of small defocused lights

We investigated influences of optics and surround area on color appearance of defocused, small narrow band photopic lights (1’ arc diameter, λmax 510 - 628 nm) centered within a black annulus and surrounded by a white field. Participants included seven normal trichromats with L- or M-cone biased ratios. We controlled chromatic aberration with elements of a Powell achromatizing lens and corrected higher-order aberrations with an adaptive-optics system. Longitudinal chromatic aberrations, but not monochromatic aberrations, are involved in changing appearance of small lights with defocus. Surround field structure is important because color changes were not observed when lights were presented on a uniform white surround

Relationship among CFH and ARMS2 genotypes, macular pigment optical density, and neuroretinal function in persons without age-related macular degeneration

Purpose: To determine whether there is a difference in neuroretinal function and in macular pigment optical density between persons with high- and low-risk gene variants for age-related macular degeneration (AMD) and no ophthalmoscopic signs of AMD, and to compare the results on neuroretinal function to patients with manifest early AMD. Methods and Participants: Neuroretinal function was assessed with the multifocal electroretinogram (mfERG) for 32 participants (22 healthy persons with no AMD and 10 early AMD patients). The 22 healthy participants with no AMD had high- or low-risk genotypes for either CFH (rs380390) and/or ARMS2 (rs10490924). Trough-to-peak response densities and peak-implicit times were analyzed in 5 concentric rings. Macular pigment optical densitometry was assessed by customized heterochromatic flicker photometry. Results: Trough-to-peak response densities for concentric rings 1 to 3 were, on average, significantly greater in participants with high-risk genotypes than in participants with low-risk genotypes and in persons with early AMD after correction for age and smoking (p<0.05). The group peak- implicit times for ring 1 were, on average, delayed in the patients with early AMD compared with the participants with high- or low-risk genotypes, although these differences were not significant. There was no significant correlation between genotypes and macular pigment optical density. Conclusion: Increased neuroretinal activity in persons who carry high-risk AMD genotypes may be due to genetically determined subclinical inflammatory and/or histological changes in the retina. Neuroretinal function in healthy persons genetically susceptible to AMD may be a useful additional early biomarker (in combination with genetics) before there is clinical manifestation